Current medical devices fabricated from prior art biological tissues tend to suffer from various limitations, due in part to the limited properties of the materials from which they are fabricated. Materials with improved properties would enable development of new and enhanced devices which are not possible with biomaterials used today. For example, percutaneous heart valves are under development to enable minimally-invasive replacement of damaged or diseased heart valves. A critical dimension of the percutaneous technology is to be able to deliver the device in a small diameter catheter so that it can be threaded through the arterial system and positioned within the heart before expansion. As described by Chiam and Ruiz, Percutaneous Transcatheter Aortic Valve Implantation, Journal of American College of Cardiovascular Interventions, volume 1, pp 341-50, 2008, early percutaneous heart valves were 25F (French, or about 8.4 mm in diameter), which compares poorly with current catheter-based interventions, such as stents and the like, which are 4-6F (1.4-2.0 mm) in size. Indeed, Kroger et al, in Diameter of occluded superficial femoral arteries limits percutaneous recanalization, Journal of Endovascular Therapeutics, volume 9, pp 369-74, 2002, report that patients with peripheral arterial disease have an average femoral artery diameter of 4.5 mm in diseased vessels and a vessel diameter of 5.7 mm in non-diseased arteries. Therefore to treat patients without vessel disease, a percutaneous valve needs to be less than 5.7 mm in diameter, or less than 17F size. To treat patients with vessel disease, the compressed valve diameter should be less than 4.5 mm, which would require a 13F diameter valve. Since patients requiring heart valve replacement frequently have comorbidities such as vessel disease, a technology that cannot be introduced into a diseased vessel would fail to treat the majority of the patient population. As current stents are able to collapse to a 4-6F size, the limiting factor in the ability to provide this important new therapy to patients is the ability to reduce the collapsed size of the valve. Since it is already possible within the prior art technologies to create a stent which can meet the size criterion, the limiting factor is the tissue. Therefore, a tissue that is strong, durable, flexible and ultrathin, would be a material which would enable percutaneous valve technologies to develop the minimal profile size required to treat these patients.
In the area of soft tissue repair and orthopedics, new biomaterials which are strong, durable, flexible and thin are also needed. Currently extracellular matrix (ECM) graft materials are approved for augmentation or replacement of soft tissue structures, such as tendon and ligament repair, bladder and breast reconstruction, skin grafting, and general soft tissue reinforcement of defects in organ walls, such as abdominal and thoracic walls. As described by J H Yoder et al, Nonlinear and anisotropic tensile properties of graft materials used in soft tissue applications, Clinical Biomechanics, volume 25, pp 378-82, 2010, the available ECM materials have limits on the critical properties needed for these applications, including strength, flexibility, durability or thickness, and are, therefore, less ideal for the intended repairs. For example, many allogenic skin graft materials do not have the desired strength for high stress applications requiring long term durability. Acellularized porcine small intestine submucosa (SIS) is used for some applications, but requires many layers to be laminated together to provide sufficient tensile strength for repair. Unfortunately, laminating 4, 8 or 10 layers of SIS tissue yields a stiff resulting laminate with limited flexibility. Equine pericardium has desirable strength characteristics, but is unacceptably thick for some applications. Having access to ECM graft materials which are strong, durable, flexible and ultrathin would enable new and improved soft tissue repair and reconstruction devices to be fabricated without the inherent limitations of current technologies.
A third area where biomaterials with enhanced properties would enable the development of important new technologies is in the area of tissue engineering. Tissue engineering is defined as an interdisciplinary field that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function or a whole organ (R P Lanza, R Lander, W L Chick, editors, Principles of Tissue Engineering, Academic Press, 1997). Tissue engineering is a large and growing field of research, and covers diverse applications in the areas of the cardiovascular system (such as tissue engineered heart valves and vessels), the musculoskeletal system (tissue engineered bone, cartilage, connective tissues, tendons and ligaments), ophthalmology (such as tissue engineered cornea and other ocular tissues), the nervous system (such as in tissue engineered implants for repair of spinal cord defects or peripheral nervous tissue regeneration), periodontal and dental applications (tissue engineered bone, implants, and surrounding soft tissues), wound repair (tissue engineered skin, dermis, or connective tissues), endocrinology (such as tissue engineered pancreas and parathyroid), the gastrointestinal system (tissue engineered intestine and liver), and the kidney and genitourinary system. Tissue engineering became a field in its own right once scientists came to appreciate the importance of the extracellular matrix as a crucial determinant for enabling cellular cooperation in multicellular complexes to carry out their programs for cell division and differentiation. Eugene Bell quickly identified the value of acellular materials which could be implanted in the body as percursors of tissue replacements, and to have them recruit appropriate cells from neighboring tissues or circulating fluids, thereby enabling the reorganization and replacement of tissues and organs with the host's own cells, using the extracellular matrix material as a scaffold (Principles of Tissue Engineering, foreword, 1997). Another use of extracellular matrix materials in tissue engineering is to apply living cells to the scaffold material outside of the body, in a suitably designed bioreactor, where the cells can then proliferate and differentiate, remodeling the scaffold into the desired tissue or organ. Upon reaching a certain stage of maturity, the living cell-scaffold construct is implanted in the body to serve its intended function (Fred Schoen, ch 8, Tissue Engineering in Biomaterials Science: An Introduction to Materials in Medicine, 2nd edition, Elsevier Press, 2004). Regardless of the approach, the ECM scaffold is a critically important element in all tissue engineered constructs. Providing adequate strength, durability, and flexibility during the remodeling process is essential for successful incorporation of a tissue engineered replacement tissue or organ.
To-date, materials used as scaffolds in tissue engineering, primarily SIS tissue or biodegradable synthetic polymers, are severely limited in application because of the lack of strength and durability. Complicated pulsing or flowing bioreactors are currently utilized in an effort to stimulate production of ECM materials for strength, but these systems require complex equipment with long culturing times in order to generate tissues with some minimum mechanical strength. A frequent problem with biodegradable polymers is that they degrade faster than the cells can synthesize replacement matrix, resulting in mechanical failure. Materials which can be utilized in transplant as scaffolds and that do not require complex culturing conditions and that already contain the desired combination of strength, flexibility and composition would be a significant improvement over scaffold materials currently available. Tissue materials that are strong, durable, flexible and ultrathin would greatly enable the use of tissue engineering principles and concepts to the create of commercial products and therapies.